The overall objective of this grant application is to investigate the myogenic and neurohormonal mechanisms of control of colonic motility in health and disease. Of particular interest are the giant migrating contractions (GMCs) and colonic motor complexes. Both motor patterns play a significant role in the physiology and pathophysiology of colonic motility. The giant migrating contractions produce mass movements and defecation. A higher than normal frequency of GMCs produces diarrhea and urgency while a lower than normal frequency has been associated with constipation. The stimulation of giant migrating contractions and their more proximal origin in the colon are major factors in producing diarrhea, urgency and abdominal discomfort in experimental models of acute inflammation, and ulcerative colitis. The descending inhibition preceding giant migrative contractions is important in mass movements because it relaxes the receiving segment to accommodate a large volume without stimulating nociceptors. Colonic migrating and non-migrating motor complexes mix and stir colonic contents and propel them slowly in the caudad direction. Our specific aims for the next four years are to investigate l) the neurohormonal mechanisms of initiation and propagation of giant migrating contractions, and 2) nonadrenergic non-cholinergic mechanisms of inhibition of colonic phasic contractions and production of descending inhibition that precedes giant migrating contractions. The goal in the first aim is to investigate the enteric, and central neural control of initiation and propagation of giant migrating contractions. These goals will be achieved by close-intraarterial and intracerebroventricular injections of specific neurotransmitters, receptor antagonists, mediators of stress response, selective myotomies and myenteric neurectomies, and bilateral pelvic nerve section. The second aim will be achieved by close intraarterial injections of nitric oxide and related compounds, vasoactive intestinal polypeptide (VIP) and VIP antagonists and inhibitors of nitric oxide synthase and other specific antagonists to examine the organization of non-adrenergic non-cholinergic nerves, and their role in producing descending inhibition produced by GMCs and balloon distension. The experiments will be done in surgically instrumented conscious dogs because the GMCs and colonic motor complexes occur only in the conscious state. Our grant proposal addresses investigation of several important and significant aspects of myogenic, neural and hormonal control of colonic motility in health and disease, such as constipation, diarrhea, IBS and IBD. New insights into these mechanisms will help in more precise diagnosis of colonic motility disorders and in proposing appropriate pharmaceutical agents and surgical procedures to normalize colonic motility in disease.